Cerebral aneurysm rupture and subarachnoid hemorrhage (SAH) inflict disability and death upon thousands of individuals each year. The consequences of subarachnoid hemorrhage (SAH) following cerebral aneurysm rupture are devastating, with mortality rates as high as 50% and the majority of survivors left with moderate to severe disability (Hop J W, Rinkel G J, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997; 28:660-664). Cerebral vasospasm, characterized as a delayed and sustained arterial constriction, is a major contributor to these high morbidity and mortality rates associated with SAH and current therapies in the treatment of this phenomenon are less than ideal (Dietrich H H, Dacey R G, Jr. Molecular keys to the problems of cerebral vasospasm. Neurosurgery. 2000; 46:517-530; Macdonald R L, Weir B K. A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke. 1991; 22:971-982; Treggiari-Venzi M M, Suter P M, Romand J A. Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care. Neurosurgery. 2001; 48:249-261.). In addition to vasospasm in large diameter arteries, enhanced constriction of resistance arteries within the cerebral vasculature may contribute to decreased cerebral blood flow and the development of delayed neurological deficits following SAH. Classically, cerebral vasospasm has been diagnosed in SAH patients by the use of angiography to detect cerebral artery narrowing.
In vitro, elevation of intravascular pressure within a physiological range (60 to 100 mmHg) constricts small diameter cerebral arteries in the absence of other vasoactive stimuli. In cerebral arteries from healthy animals, increased intravascular pressure leads to vascular smooth muscle membrane potential depolarization and increased global cytosolic free Ca2+ concentration ([Ca2+]i) due to an increase in the open-state probability of L-type voltage-dependent Ca2+ channels (VDCCs) (Brayden J E, Wellman G C. J Cereb Blood Flow Metab. 1989; 9:256-263; Harder D R. Circ Res. 1984; 55:197-202; Knot H J, et. al., J Physiol (Lond). 1998; 508:199-209.). L-type VDCC antagonists cause a maximal decrease in [Ca2+]i and abolish pressure- and agonist-induced constriction in small diameter arteries (Knot H J, et. al., J Physiol (Lond). 1998; 508:199-209; Gokina N I, Knot H J, Nelson M T, Osol G. Am J Physiol. 1999; 277:H1178-H1188; Hill M A, et. al., J Appl Physiol. 2001; 91:973-983.). While L-type Ca2+ channels are widely accepted to be the dominant type of voltage-dependent Ca2+ channels expressed in arterial myocytes, studies have also reported the presence of T-type (Chen C C, et. al., Science. 2003; 302:1416-1418; Hansen P B, et. al., Circ Res. 2001; 89:630-638.), P/Q-type (Hansen P B, et. al., Circ Res. 2000; 87:896-902) and nifedipine-resistant high voltage-activated Ca2+ Channels (Itonaga Y, et. al., Life Sci. 2002; 72:487-500; Morita H, et. al., Circ Res. 1999; 85:596-605; Simard J M. Pflugers Arch. 1991; 417:528-536.). Expression of L-type Ca2+ channels in vascular smooth muscle has been reported to change both during development (Blood A B, et. al., Am J Physiol Regul Integr Comp Physiol. 2002; 282:R131-R13) and hypertension (Pratt P F, et. al., Hypertension. 2002; 40:214-219.).